Whole-exome sequencing identifies PRSS56 variants in Chinese patients with microphthalmia

This study aimed to elucidate the genetic and clinical profiles of Chinese patients with microphthalmia harbouring PRSS56 variants and investigate the genotype‒phenotype correlation. Whole-exome sequencing (WES) was performed in patients with microphthalmia and available family members to assess coding regions and adjacent intronic splice boundaries for variant detection and downstream interpretation. The axial lengths (ALs) of all the probands and available family members were measured. The genotype‒phenotype correlation was explored by statistical analysis, and protein structure prediction was analysed in silico. Seven PRSS56 variants were detected across four of the seven families, including two novel candidate variants (c.175G > A:p.E59K and c.1030 C > A:p.P344T) and five previously reported variants. Variant p.Q356Pfs152 was found in two unrelated families and was the most frequent. The mutational spectrum frequency in the Chinese population differed from that in other ethnic groups worldwide. The average AL was 17.82 ± 1.51 mm. In an exploratory pooled analysis combining the current cohort with previously published cases, eyes with biallelic LoF variants showed shorter ALs than eyes with missense variants. Variants p.G107V and p.E396K, which were reported exclusively in Chinese microphthalmia cases, were predicted to destabilize the PRSS56 protein. Among nine individuals from seven families, seven PRSS56 variants were identified in four families, underscoring the significant genetic diversity within the Chinese population. The reported variant p.Q356Pfs*152 had the highest frequency in our cohort. Our findings expand current understanding of PRSS56-associated microphthalmia and provide valuable information for prenatal diagnosis and future therapeutic strategies.